Parathyroid hormone (PTH) is a linear polypeptide containing 81 amino-acid residues. This hormone acts to maintain calcium homeostasis in vertebrates through interaction with specific receptors in kidney, bone, and possibly other tissues. Present evidence indicates that interaction of PTH with its receptors triggers membrane-associated activation of adenylate cyclase, with cyclic-AMP then mediating biological responses to hormone stimulation. This study will explore the nature of the hormone-receptor interaction by means of a PTH structure-function study. Fragments and analogs of PTH will be synthesized by the solid-phase method. After purification and characterization, these peptides will be investigated for PTH receptor-binding properties in vitro. Those which bind will be studied for PTH agonist and antagonist activities in vitro and in vivo. Specifically, we will focus on the nature of the receptor-binding process. Recent data indicate that the major binding function of PTH is centered in the 20-27 region of the molecule. This is the same region of PTH in which an adrenocorticotropin (ACTH)-homologous sequence occurs. We have shown that in high concentrations, ACTH (1-24) binds competitively to the PTH receptor in renal plasma membranes. Common sequences in the two peptide hormones may account for their interaction with the same receptor. These observations will be among those used in the design of analogs of PTH fragments which vary in their receptor-binding characteristics. These data gathered in vitro will be used to attempt development of an effective PTH inhibitor in vivo. Such an inhibitor would have important implications in clinical states of PTH overactivity.